Inhibitors of Advanced Glycation End Products

ABSTRACT

The present invention provides compounds of the formula, 
     
       
         
         
             
             
         
       
     
     wherein A, B, G, R 2 , R 6 , and X are defined herein, pharmaceutical compositions of the same, and methods for treating or inhibiting development of AGE- and/or ALE-associated complications in subjects in need thereof.

CROSS-REFERENCE

This application is a continuation to U.S. patent application Ser. No.11/825,045 filed Jul. 3, 2007, which claims priority to ProvisionalPatent Application Ser. No. 60/819,437 filed Jul. 7, 2006, incorporatedby reference herein in its entirety.

FIELD OF THE INVENTION

This application relates to the fields of chemistry, medicine, renaldisease, vascular disease, hyperlipidemia, hyperglycemia, advancedglycation end-products, and advanced lipoxidation end-products.

BACKGROUND OF THE INVENTION

Advanced glycation end-products (AGEs) are carbohydrate-derived chemicalmodifications and crosslinks that accumulate in long-lived tissueproteins during normal aging. The increased rate of accumulation of AGEsduring hyperglycemia is implicated in the development of long-termcomplications of diabetes, including but not limited to retinopathy,nephropathy, neuropathy, atherosclerosis, and cardiovascular disease. Inaddition, AGE formation has been implicated in a number of otherpathologies, such as normal aging processes, arthritis, connectivetissue disease, amyloidoses, and neurodegenerative amyloid diseases,such as Alzheimer's.

Advanced lipoxidation end products (ALEs) are lipid-derived chemicalmodifications and crosslinks that also accumulate in long-lived tissueproteins during normal aging, and are associated with hyperlipidemia,vascular disease, and renal disease in both diabetic and non-diabeticanimal models. It is now recognized that some compounds, such asN^(ε)-(carboxymethyl)lysine (CML) and N^(ε)-(carboxyethyl)lysine (CEL),may be derived from either carbohydrates or lipids, leading to theirdesignation as AGE/ALEs. Other compounds, such as pentosidine, appear tobe true AGEs, while other compounds, such as malondialdehyde-lysine(MDA-Lys) and hydroxynonenal-lysine (HNE-Lys), are acknowledged to beALEs, derived exclusively from lipids.

The elucidation of the pathogenic mechanisms of AGE and ALE-associatedcomplications associated with hyperglycemia and/or hyperlipidemia iscritical for developing rational therapy for their treatment andprevention. However, there is no consensus at present on the relativeimportance of the different possible pathogenic mechanisms thatpotentially contribute to these diabetic complications.

The compound pyridoxamine has recently been shown to inhibit both AGEand ALE formation in vitro, and to be useful for treating and preventingAGE and ALE-associated complications in hyperglycemic, hyperlipidemic,and hyperglycemic-hyperlipidemic animal models. (See, for example, U.S.Pat. No. 5,985,857; WO 00/21516; WO 00/23063) Such complicationsinclude, but are not limited to, diabetic nephropathy, proteinuria,impaired glomerular clearance, retinopathy, neuropathy, atherosclerosis,diabetes-associated hyperlipidemia, oxidative modification of proteins,urinary stone disease, obesity-related complications, proliferation orsmooth muscle cells in the aorta, coronary artery occlusion, andhypertension; and dialysis-related disorders including dialysis-relatedcardiac morbidity and mortality, dialysis-related amyloidosis,dialysis-related increases in permeability of the peritoneal membrane ina dialysis patient, renal failure progression in a dialysis patient, andinhibiting ultrafiltration failure and peritoneal membrane destructionin a dialysis patient.

However, there remains a need in the art for further options to treat orinhibit development of AGE- and ALE-associated complications in patientsin need thereof, particularly patients with hyperglycemia and/orhyperlipidemia.

SUMMARY OF THE INVENTION

The present invention provides compounds, pharmaceutical compositions,and methods for treating or inhibiting development of AGE- and/orALE-associated complications in a subject in need thereof. Thus, theinvention provides novel compounds, detailed below, and pharmaceuticalcompositions thereof. In a preferred embodiment, the methods compriseadministering one or more of the compounds or pharmaceuticalcompositions of the invention to subjects suffering from hyperglycemiaand/or hyperlipidemia. The invention further comprises methods oftreating or inhibiting development of disorders including diabeticnephropathy, proteinuria, impaired glomerular clearance, retinopathy,neuropathy, atherosclerosis, diabetes-associated hyperlipidemia,oxidative modification of proteins, arthritis, connective tissuediseases, amyloidosis, urinary stone disease, obesity-relatedcomplications, proliferation of smooth muscle cells in the aorta,coronary artery occlusion, and hypertension; and dialysis-relateddisorders including dialysis-related cardiac morbidity and mortality,dialysis-related amyloidosis, dialysis-related increases in permeabilityof the peritoneal membrane in a dialysis patient, renal failureprogression in a dialysis patient, and inhibiting ultrafiltrationfailure and peritoneal membrane destruction in a dialysis patient. Saidmethods comprise administering an effective amount of one or morecompounds of the present invention, or a pharmaceutically acceptablesalt thereof, to a subject in need of such treatment.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the chemical structures for several compoundsreferenced herein.

FIG. 2 is a graphical representation providing comparative cell toxicitydata for pyridoxamine (PM), BST-4997, BST-998, BST-146, BST-605.

FIG. 3 is a graphical representation of the effect of BST-605 on therestoration of nerve conduction velocity in motor (sciatic nerve)neurons in streptozotocin diabetic rats.

FIG. 4 is a graphical representation of the effect of BST-605 on therestoration of nerve conduction velocity in sensory (saphenous) neuronsin streptozotocin diabetic rats.

FIG. 5 is a graphical comparison of the effect of BST-605, BST-4997, andpyridoxamine on the restoration of nerve conduction velocity in motor(sciatic nerve) neurons in streptozotocin diabetic rats.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the invention provides the compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein

X is N, N—O, or CR¹;

G is —H, heterocycle, or —(C₁-C₆)alkyl, wherein the heterocycle andalkyl are optionally substituted with at least one group independentlyselected from the group consisting of -halogen, —OR^(G), —N(R^(G))₂,—SR^(G), —S(O)R^(G), —S(O)₂R^(G), —COOR^(G), —CON(R^(G))₂, and—(C₁-C₆)alkyl-OR^(G), wherein R^(G) is hydrogen, —(C₁-C₆)alkyl, or—C(O)(C₁-C₆)alkyl;A is of formula (Ia),

wherein

Y is N or N-oxide; and

ring C is:(i) monocyclic;(ii) saturated; and(iii) contains 1 or 2 total heteroatoms, and 5 or 6 total atoms, wherein

-   -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C) wherein        -   R^(N1) is —H, -oxide, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl,                —(C₃-C₈)cycloalkyl, -heterocycle, -aryl, -heteroaryl,                —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,                -heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or                -aryl(C₁-C₆)alkoxycarbonyl, wherein                -   R^(N1) is optionally substituted with one or more                    groups which are independently -halogen, —OR^(N12),                    —N(R^(N12))², —COOR^(N12), —CON(R^(N12))₂,                    —SR^(N12), —S(O)R^(N12), —S(O)₂R^(N12), —NO₂, —CN,                    —(C₁-C₆)alkyl, —(C₁-C₆)alkyl-OR^(N12), aryl,                    —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl,                    —(C₁-C₆)alkanoyl, or -aroyl, wherein R^(N12) is                    hydrogen, —(C₁-C₆)alkyl, or —C(O)(C₁-C₆)alkyl;    -   each R^(C) is independently —Z¹-M-Z²—R^(Z), wherein        -   M is —C(O)—, —C(S)—, —S(O)—, —S(O)₂—, or absent,            -   provided when M is —S(O)—, —S(O)₂—, or absent, at least                one of Z¹ and Z² is also absent;        -   Z¹ and Z² are independently —O—, —S—, —N(R^(N′))—, or            absent, wherein            -   R^(N′) is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,                —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl,                —(C₃-C₈)cycloalkyl, -heterocycle, -aryl, -heteroaryl,                —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,                -heteroaroyl, -(C₁-C₆)alkoxycarbonyl, or                -aryl(C₁-C₆)alkoxycarbonyl, wherein                -   R^(N′) is optionally substituted with one or more                    groups which are independently -halogen, —OR, —COOR,                    —CONR₂, —SR, —S(O)R, —S(O)₂R, —NR₂, —NO₂, —CN,                    —(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl,                    —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl,                    -(C₁-C₆)alkanoyl, or -aroyl                -    wherein each R is independently —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl, wherein the alkyl and alkoxy are                    optionally substituted with one or more R′;                -    wherein each R′ is independently halogen, —OR″,                    —CN, —COR″, —COOR″, —CONR″₂, or NR″₂, wherein                -    each R″ is independently —H, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl;        -   R^(Z) is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl,            —(C₁-C₆)alkylaryl, -heterocycle, -aryl, or -heteroaryl,            wherein            -   R^(Z) is optionally substituted with at least one R^(Z),                wherein                -   each R^(Z′) is independently -halogen, —OR,                    —(C₁-C₆)alkoxy, —C(O)OR, —C(O)R, —C(O)NR₂, —S(O)₂R,                    —OS(O)₂R, -cyano, -nitro, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl,                    -heterocycloalkyl, or heteroaryl,                -    wherein R^(Z′) is optionally substituted with one                    or more R′,    -   or any two R^(C) attached to the same carbon, taken together, is        oxo or ═N(R^(N4)), wherein        -   R^(N4) is —H, 13 OR, —N(R^(N5)), —N(R^(N5))₂,            —(C₂-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl,            —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl, -heterocycle, -aryl,            or -heteroaryl, wherein            -   R^(N4) is optionally substituted with one or more groups                which are independently -halogen, —OH, -amino,                —(C₁-C₆)alkylamino, —(C₁-C₆)dialkylamino, —NO₂, —CN,                —(C₁-C₆)alkyl, -aryl, -heteroaryl, -heterocycle,                —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                —(C₁-C₆)alkanoyl, or -aroyl; and            -   each R^(N5) is independently —H, —(C₁-C₆)alkyl,                —(C₂-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl,                —(C₁-C₆)alkanoyl, or —(C₃-C₈)cycloalkyl;                B is of formula (Ib),

whereinring D is (i) monocyclic, and

-   -   (ii) saturated, unsaturated, or aromatic;        R^(C′) is R^(C), provided that R^(C′) is not aryl or heteroaryl;        G¹, G², and G³ each are independently N, O, CR³, C(R³)₂, or        NR^(N′), wherein    -   each R³ is independently —Z³-M-Z⁴—R^(Z),        -   provided when M is —S(O)—, —S(O)₂—, or absent, at least one            of Z³ and Z⁴ is also absent;        -   Z³ and Z⁴ are independently —O—, —S—, —N(R^(N3))— or absent,            wherein            -   R^(N3) is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,                —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl,                —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,                -heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or                -aryl(C₁-C₆)alkoxycarbonyl, wherein                -   R^(N3) is optionally substituted with one or more                    groups which are independently -halogen, —OH,                    -amino, —(C₁-C₆)alkylamino, —(C₁-C₆)dialkylamino,                    —NO₂, —CN, —(C₁-C₆)alkyl, -aryl, -heterocycle,                    -heteroaryl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl,                    —(C₁-C₆)alkoxy, —(C₁-C₆)alkanoyl, or -aroyl;    -   or two R³ taken together are oxo; and        bonds a, b, c, d, and e are independently a single or double        bond,        provided that    -   (i) no two consecutive atoms in ring D are both oxygen;    -   (ii) no two consecutive bonds are both double bonds;    -   (iii) if a orb is a double bond, then R^(C′) is absent; and    -   (iv) if a or e is a double bond, then R^(N′) is absent; and        R¹, R², and R⁶ are independently —H, -halogen, —NO₂, —CN, or        R^(C),        provided that when X═CR¹,    -   (i) R², R⁶, and R^(N1) are not phenyl;    -   (ii) R^(C) is not aryl, heteroaryl, heterocycle, or        (C₂-C₆)alkenyl    -   (iii) and G¹=N together, then G² is not O; and    -   (iv) two R^(C) together may not form oxo;        and provided that when X═N, and    -   (i) G¹ and G³ each are CR³, G²=N, and bonds b and d are each a        double bond, all simultaneously; or    -   (ii) G¹ is CR³, G³ is C(O), G² is NR^(N′), and bond b is a        double bond, all simultaneously;        either R² or R⁶ is not —NH-aryl or —NH-heteroaryl.

In a preferred embodiment, the invention provides the compound accordingto formula (I) wherein G is hydrogen.

In a preferred embodiment, the invention provides the compound accordingto formula (I) wherein G is a heterocycle or —(C₁-C₆)alkyl, eachoptionally substituted with at least one group independently selectedfrom the group consisting of —OR^(G), —N(R^(G))₂, —SR^(G), —S(O)R^(G),—S(O)₂R^(G), —COOR^(G), —CON(R^(G))₂, and —(C₁-C₆)alkyl-OR^(G), whereinR^(G) is hydrogen, —(C₁-C₆)alkyl, or —C(O)(C₁-C₆)alkyl.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; and G is —H.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; and G is a heterocycle or —(C₁-C₆)alkyl,each optionally substituted with at least one group independentlyselected from the group consisting of —OR^(G), —N(R^(G))₂, —SR^(G),—S(O)R^(G), —S(O)₂R^(G), —COOR^(G), —CON(R^(G))₂, and—(C₁-C₆)alkyl-OR^(G), wherein R^(G) is hydrogen, —(C₁-C₆)alkyl, or—C(O)(C₁-C₆)alkyl.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; and G is a heterocycle or —(C₁-C₆)alkyl,each optionally substituted with at least one group independentlyselected from the group consisting of —OH and —COOH.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; and G is a tetrahydrofuranyl,tetrahydropyranyl, or —(C₅-C₆)alkyl, each optionally substituted with atleast one group independently selected from the group consisting of —OHand —COOH.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N—O.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen; B is aromatic; and

-   -   G¹, G², and G³ are each independently O, N or CR³.

In preferred embodiment, the invention provides the compound accordingto formula (I), wherein X is N; G is hydrogen; and

-   -   B is imidazolyl, oxazoyl, pyrazoyl, pyrroyl, or isoxazoyl        wherein each carbon atom is substituted by R³.

In more preferred embodiment, the invention provides the compoundaccording to formula (I), wherein X is N; G is hydrogen; and

-   -   B is imidazolyl, wherein each carbon atom is substituted by R³.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is imidazolyl, wherein each carbon atom is substituted by R³;        and    -   wherein each R³ is independently R^(Z3), wherein        -   R^(Z3) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z3) is optionally substituted            with at least one R^(Z3′), wherein            -   each R^(Z3′) is independently -halogen, -cyano, —OR,                —C(O)OR, —C(O)R, —C(O)NR₂, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, or                -heterocycloalkyl.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is imidazolyl, wherein each carbon atom is substituted by R³;        and    -   R² and R⁶ are each —H, -halogen, —NO₂, —CN, or —R^(Z6) wherein        -   R^(Z6) is —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z6) is optionally substituted            with at least one R^(Z6′),            -   wherein each R^(Z6′) is independently -halogen, —OR,                —C(O)OR, —C(O)R, —(C₁-C₆)alkyl, or —(C₁-C₆)haloalkyl,                -   wherein R^(Z6′) is optionally substituted with one                    or more R′.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is imidazolyl, wherein each carbon atom is substituted by R³;        and    -   R^(N′) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,        —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl, -aryl, -heteroaryl,        —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl, -heteroaroyl,        —(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl, wherein        -   R^(N′) is optionally substituted with one or more groups            which are independently -halogen, —OR^(N″), —NR^(N″) ₂,            —NO₂, —CN, —(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl,            —(C₃-C₈)cycloalkyl, or —(C₁-C₆)haloalkyl,            -   wherein each R^(N″) is independently —H, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,                -heterocycloalkyl, aryl, or heteroaryl, wherein the                alkyl and alkoxy are optionally substituted with one or                more R′.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is imidazolyl, wherein each carbon atom is substituted by R³;    -   Y is N; and    -   ring C contains 2 heteroatoms, and 5 total atoms, wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C).

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is imidazolyl, wherein each carbon atom is substituted by R³;    -   Y is N; and    -   ring C contains 2 heteroatoms, and 6 total atoms, wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C).

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is not aromatic; and    -   G¹, G², and G³ are each independently O, N, CR³, C(R³)₂, or        N(R^(N′)).

In a preferred embodiment, the invention provides the compound accordingto formula (I), wherein X is N; G is hydrogen;

-   -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein    -   each carbon is substituted by two R³ and each nitrogen is        substituted by R^(N′).

In a more preferred embodiment, the invention provides the compoundaccording to formula (I), wherein X is N; G is hydrogen;

-   -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′); and    -   each R³ is independently R^(Z3), wherein        -   R^(Z3) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z3) is optionally substituted            with at least one R^(Z3′), wherein            -   each R^(Z3′) is independently -halogen, -cyano, —OR,                —C(O)OR, —C(O)R, —C(O)NR₂, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, or                -heterocycloalkyl.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, thiazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′); and    -   R² and R⁶ are each —H, -halogen, —NO₂, —CN, or —R^(Z6) wherein        -   R^(Z6) is —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z6) is optionally substituted            with at least one R^(Z6′),            -   wherein each R^(Z6′) is independently -halogen, —OR,                —C(O)OR, —C(O)R, —(C₁-C₆)alkyl, or —(C₁-C₆)haloalkyl,                -   wherein R^(Z6′) is optionally substituted with one                    or more R′.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′); and    -   each R^(N′) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,        —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl, -aryl, -heteroaryl,        —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl, -heteroaroyl,        —(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl, wherein        -   R^(N′) is optionally substituted with one or more groups            which are independently -halogen, —OR^(N″), —NR^(N″) ₂,            —NO₂, —CN, —(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl,            —(C₃-C₈)cycloalkyl, or —(C₁-C₆)haloalkyl,            -   wherein each R^(N″) is independently —H, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,                -heterocycloalkyl, aryl, or heteroaryl, wherein the                alkyl and alkoxy are optionally substituted with one or                more R′.

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′);    -   Y is N; and    -   ring C contains 2 heteroatoms, and 5 total atoms, wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C).

In another embodiment, the invention provides the compound according toformula (I), wherein X is N; G is hydrogen;

-   -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′);    -   Y is N; and    -   ring C contains 2 heteroatoms, and 6 total atoms, wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(G).

In another embodiment, the invention provides the compound according toformula (I), wherein X is CR¹.

In another embodiment, the invention provides the compound according toformula (I), wherein X is CR¹; and G is —H.

In another embodiment, the invention provides the compound according toformula (I), wherein X is CR¹; and G is a heterocycle or —(C₁-C₆)alkyl,each optionally substituted with at least one group independentlyselected from the group consisting of —OR^(G), —N(R^(G))₂, —SR^(G),—S(O)R^(G), —S(O)₂R^(G), —COOR^(G), —CON(R^(G))₂, and—(C₁-C₆)alkyl-OR^(G), wherein R^(G) is hydrogen, —(C₁-C₆)alkyl, or—C(O)(C₁-C₆)alkyl.

In another embodiment, the invention provides the compound according toformula (I), wherein X is CR¹; and G is a heterocycle or —(C₁-C₆)alkyl,each optionally substituted with at least one group independentlyselected from the group consisting of —OH and —COOH.

In another embodiment, the invention provides the compound according toformula (I), wherein X is CR¹; and G is a tetrahydrofuranyl,tetrahydropyranyl, or —(C₅-C₆)alkyl, each optionally substituted with atleast one group independently selected from the group consisting of —OHand —COOH.

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl.

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is aromatic; and    -   G¹, G², and G³ are each independently O, N or CR³.

In a preferred embodiment, the invention provides the compound accordingto formula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is imidazolyl, oxazoyl, pyrazoyl, pyrroyl, or isoxazoyl        wherein each carbon atom is substituted by R³.

In a more preferred embodiment, the invention provides the compoundaccording to formula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is imidazolyl wherein each carbon atom is substituted by R³;        and

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is imidazolyl wherein each carbon atom is substituted by R³;    -   each R³ is independently R^(Z3), wherein        -   R^(Z3) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z3) is optionally substituted            with at least one R^(Z3′), wherein            -   each R^(Z3′) is independently -halogen, -cyano, —OR,                —C(O)OR, —C(O)R, —C(O)NR₂, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, or                -heterocycloalkyl.

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is imidazolyl wherein each carbon atom is substituted by R³;        and    -   R² and R⁶ are each —H, -halogen, —NO₂, —CN, or —R^(Z6) wherein        -   R^(Z6) is —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z6) is optionally substituted            with at least one R^(Z6′),            -   wherein each R^(Z6′) is independently -halogen, —OR,                —C(O)OR, —C(O)R, —(C₁-C₆)alkyl, or —(C₁-C₆)haloalkyl,                -   wherein R^(Z6′) is optionally substituted with one                    or more R′.

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is imidazolyl wherein each carbon atom is substituted by R³;        and    -   R^(N′) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,        —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl, -aryl, -heteroaryl,        —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl, -heteroaroyl,        —(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl, wherein        -   R^(N′) is optionally substituted with one or more groups            which are independently -halogen, —OR^(N″), —NR^(N″) ₂,            —NO₂, —CN, —(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl,            —(C₃-C₈)cycloalkyl, or —(C₁-C₆)haloalkyl,            -   wherein each R^(N″) is independently —H, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,                -heterocycloalkyl, aryl, or heteroaryl, wherein the                alkyl and alkoxy are optionally substituted with one or                more R′.

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is imidazolyl wherein each carbon atom is substituted by R³;    -   Y is N; and ring C contains 2 heteroatoms, and 5 total atoms,        wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C).

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is imidazolyl wherein each carbon atom is substituted by R³;    -   Y is N; and ring C contains 2 heteroatoms, and 6 total atoms,        wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C).

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is not aromatic; and    -   G¹, G², and G³ are each independently O, N, CR³, C(R³)₂, or        N(R^(N′)).

In a preferred embodiment, the invention provides the compound accordingto formula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′).

In a more preferred embodiment, the invention provides the compoundaccording to formula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′); and    -   each R³ is independently R^(Z3), wherein        -   R^(Z3) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z3) is optionally substituted            with at least one R^(Z3′), wherein            -   each R^(Z3′) is independently -halogen, -cyano, —OR,                —C(O)OR, —C(O)R, —C(O)NR₂, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, or                -heterocycloalkyl.

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′); and    -   R² and R⁶ are each —H, -halogen, —NO₂, —CN, or —R^(Z6) wherein        -   R^(Z6) is —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl,            or -heteroaryl, wherein R^(Z6) is optionally substituted            with at least one R^(Z6′),            -   wherein each R^(Z6′) is independently -halogen, —OR,                —C(O)OR, —C(O)R, —(C₁-C₆)alkyl, or —(C₁-C₆)haloalkyl,                -   wherein R^(Z6′) is optionally substituted with one                    or more R′.

In a preferred embodiment, the invention provides the compound accordingto formula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′); and    -   each R^(N′) is independently —H, —(C₁-C₆)alkyl,        —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl, -aryl,        -heteroaryl, —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,        -heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or        -aryl(C₁-C₆)alkoxycarbonyl, wherein        -   R^(N′) is optionally substituted with one or more groups            which are independently -halogen, —OR^(N″), —NR^(N″) ₂,            —NO₂, —CN, —(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl,            —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl,            -   wherein each R^(N″) is independently —H, —(C₁-C₆)alkyl,                —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, or                —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                heteroaryl, wherein the alkyl and alkoxy are optionally                substituted with one or more R′.

In a more preferred embodiment, the invention provides the compoundaccording to formula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′);    -   Y is N; and    -   ring C contains 2 heteroatoms, and 5 total atoms, wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C).

In another embodiment, the invention provides the compound according toformula (I), wherein G is hydrogen; X is CR¹, wherein

-   -   R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴, —C(O)N(R⁴)₂,        —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein        -   each R⁴ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,            -   —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,                -aryl, or -heteroaryl, wherein                -   R⁴ is optionally substituted with at least one                    group, each of which are independently -halogen,                    —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,                    —OS(O)₂R⁴¹, -cyano, -nitro, —(C₁-C₆)alkyl, or                    —(C₁-C₆)haloalkyl,                -    wherein R⁴¹ is —H, —(C₁-C₆)alkyl,                    —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,                    —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or                    heteroaryl;    -   B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,        isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl,        wherein        -   each carbon is substituted by two R³ and each nitrogen is            substituted by R^(N′);    -   Y is N; and    -   ring C contains 2 heteroatoms, and 6 total atoms, wherein    -   the remaining heteroatom moiety is O, S, or NR^(N1), and the        carbon atoms are each optionally substituted with one or two        R^(C).

In another embodiment, the invention provides the compound according toformula (I), which is4-(1H-imidazol-2-yl)-2-methyl-5-((4-methylpiperazin-1-yl)methyl)pyridin-3-ol.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising one or more compounds of the invention, asdisclosed above and a pharmaceutically acceptable carrier. Preferredembodiments of the pharmaceutical compositions are described below.

In a further aspect, the present invention provides methods for treatingor inhibiting development of one or more AGE- and/or ALE-associatedcomplications in subject in need thereof comprising administering one ormore compounds or pharmaceutical compositions of the invention to asubject in need thereof. As used herein, the phrase “AGE and/or ALEassociated complications” includes, but is not limited to acceleratedprotein aging, retinopathy, nephropathy, proteinuria, impairedglomerular clearance, neuropathy, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, atherosclerosis, cardiovascular disease, andneurodegenerative amyloid diseases, such as Alzheimer's disease,diabetes-associated hyperlipidemia, oxidative modification of proteins,arthritis, connective tissue diseases, amyloidosis, urinary stonedisease, obesity-related complications proliferation or smooth musclecells in the aorta, coronary artery occlusion, oxidative stress-relatedconditions, and hypertension; and dialysis-related disorders includingdialysis-related cardiac morbidity and mortality, dialysis-relatedamyloidosis, dialysis-related increases in permeability of theperitoneal membrane in a dialysis patient, renal failure progression ina dialysis patient, and inhibiting ultrafiltration failure andperitoneal membrane destruction in a dialysis patient.

In a further aspect, the invention provides methods for treating orinhibiting development of one or more of diabetic nephropathy,proteinuria, impaired glomerular clearance, retinopathy, neuropathy,atherosclerosis, diabetes-associated hyperlipidemia, oxidativemodification of proteins, arthritis, connective tissue diseases,amyloidosis, urinary stone disease, obesity-related complicationsproliferation or smooth muscle cells in the aorta, coronary arteryocclusion, oxidative stress-related disorders and hypertension; anddialysis-related disorders including dialysis-related cardiac morbidityand mortality, dialysis-related amyloidosis, dialysis-related increasesin permeability of the peritoneal membrane in a dialysis patient, renalfailure progression in a dialysis patient, and inhibitingultrafiltration failure and peritoneal membrane destruction in adialysis patient, wherein the methods comprise administering aneffective amount of one or more compounds of the present invention, or apharmaceutically acceptable salt thereof, to a subject in need of suchtreatment.

In a preferred embodiment, the methods are used to treat patientssuffering from hyperlipidemia and/or hyperglycemia or theircomplications, or to inhibit development of complications arising fromhyperlipidemia and/or hyperglycemia, such as those described above.

While the methods of this aspect of the present invention are notlimited by a specific mechanism, it is believed that the compounds ofthe invention are useful in treating or inhibiting development of thesecomplications based on their ability to inhibit AGE and/or ALEformation, and thus to inhibit the development or progression ofcomplications associated with accumulation of AGEs and/or ALEs.

DEFINITIONS

As used herein, “treat” or “treating” means accomplishing one or more ofthe following: (a) reducing the severity of the disorder; (b) limitingor preventing development of symptoms characteristic of the disorder(s)being treated; (c) inhibiting worsening of symptoms characteristic ofthe disorder(s) being treated; (d) limiting or preventing recurrence ofthe disorder(s) in patients that have previously had the disorder(s);and (e) limiting or preventing recurrence of symptoms in patients thatwere previously symptomatic for the disorder(s).

As used herein, the term “inhibiting development of” means to prevent orto minimize development of the disorder or complication in individualsat risk of developing the disorder or complication.

The term “absent” as used herein means the group is replaced by a singlebond. If replacing the group with a bond results in two connectedmoieties both defined as bonds, then -bond-bond- groups are understoodto reduce to a single bond.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond. Representative examples of alkenyl include,but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl,3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkanoyl” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butyryl, 2-pentynyl, and 1-butyryl.

The term “aryl,” as used herein, means phenyl or a bicyclic aryl or atricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to acycloalkyl, or a phenyl fused to a cycloalkenyl. The bicyclic aryl isattached to the parent molecular moiety through any carbon atomcontained within the bicyclic aryl. Representative examples of thebicyclic aryl include, but are not limited to, dihydroindenyl, indenyl,naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. The tricyclicaryl is anthracene or phenanthrene, or a bicyclic aryl fused to acycloalkyl, or a bicyclic aryl fused to a cycloalkenyl, or a bicyclicaryl fused to a phenyl. The tricyclic aryl is attached to the parentmolecular moiety through any carbon atom contained within the tricyclicaryl. Representative examples of tricyclic aryl ring include, but arenot limited to, azulenyl, dihydroanthracenyl, fluorenyl, andtetrahydrophenanthrenyl.

The term “arylalkoxycarbonyl” as used herein, means an arylalkoxy group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyland naphth-2-ylmethoxycarbonyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “aroyl” as used herein, means an aryl group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of arylcarbonyl include, but arenot limited to, benzoyl and naphthoyl.

The term “cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons, examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The term “cycloalkanoyl” as used herein, means cycloalkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,2-cyclobutylcarbonyl, and cyclohexylcarbonyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 memberedring. The 5 membered ring consists of two double bonds and one, two,three or four nitrogen atoms and optionally one oxygen or sulfur atom.The 6 membered ring consists of three double bonds and one, two, threeor four nitrogen atoms. The 5 or 6 membered heteroaryl is connected tothe parent molecular moiety through any carbon atom or any nitrogen atomcontained within the heteroaryl. Representative examples of monocyclicheteroaryl include, but are not limited to, furyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroarylconsists of a monocyclic heteroaryl fused to a phenyl, or a monocyclicheteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to acycloalkenyl, or a monocyclic heteroaryl fused to a monocyclicheteroaryl. The bicyclic heteroaryl is connected to the parent molecularmoiety through any carbon atom or any nitrogen atom contained within thebicyclic heteroaryl. Representative examples of bicyclic heteroarylinclude, but are not limited to, benzimidazolyl, benzofuranyl,benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl,dihydroisoquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl,naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.

The term “heteroaryloyl” as used herein, means a heteroaryl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofheteroarylcarbonyl include, but are not limited to, fur-3-ylcarbonyl,1H-imidazol-2-ylcarbonyl, 1H-imidazol-4-ylcarbonyl,pyridin-3-ylcarbonyl, 6-chloropyridin-3-ylcarbonyl,pyridin-4-ylcarbonyl, (6-(trifluoromethyl)pyridin-3-yl)carbonyl,(6-(cyano)pyridin-3-yl)carbonyl, (2-(cyano)pyridin-4-yl)carbonyl,(5-(cyano)pyridin-2-yl)carbonyl, (2-(chloro)pyridin-4-yl)carbonyl,pyrimidin-5-ylcarbonyl, pyrimidin-2-ylcarbonyl, thien-2-ylcarbonyl, andthien-3-ylcarbonyl.

The term “heterocycle” as used herein, means a monocyclic, and 3, 4, 5,6 or 7 membered ring containing at least one heteroatom independentlyselected from the group consisting of O, N, and S. The 3 or 4 memberedring contains 1 heteroatom selected from the group consisting of O, Nand S. The 5 membered ring contains zero or one double bond and one, twoor three heteroatoms selected from the group consisting of O, N and S.The 6 or 7 membered ring contains zero, one or two double bonds and one,two or three heteroatoms selected from the group consisting of O, N andS. The heterocycle is connected to the parent molecular moiety throughany carbon atom or any nitrogen atom contained within the monocyclicheterocycle. Representative examples of heterocycles include, but arenot limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl,pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, andtrithianyl.

The term “heterocycloyl” as used herein, means a heterocycle, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein.

“Oxidative stress” is defined as specific increases in reactive oxygenspecies and derived free radicals. Oxidative-stree related conditionsinclude, but are not limited to atherosclerosis, ischemia-reperfusioninjury, inflammatory diseases such as arthritis, cancer, exposure toionizing radiation and/or chemotherapeutic agents, pulmonary adultrespiratory distress syndrome (ARDS), myocardial infarction and strokes,pancreatitis, or intestinal ulceration, and aging. (See, for example,U.S. Pat. Nos. 5,700,654 and 5,462,946).

The term “oxide” as used herein, means an —O moiety; for example,attachment of an oxide group to a nitrogen forms an N-oxide compound, asis familiar to those skilled in the art. In such compounds, the oxygenhas a formal negative charge and the nitrogen has a formal positivecharge, therefore, the entire compound has a zero net charge.

The term “oxo” as used herein, means an ═O moiety.

Pharmaceutical Compositions and Administration

The instant compounds can be administered individually or incombination, usually in the form of a pharmaceutical composition. Suchcompositions are prepared in a manner well known in the pharmaceuticalart and comprise at least one active compound.

The compounds of the invention can be administered as the sole activepharmaceutical agent, or they can be used in combination with one ormore other compounds useful for carrying out the methods of theinvention, including but not limited to pyridoxamine, aminoguanidine,compounds disclosed in WO 2004/019889 (including but not limited to BST4996, BST 4997, and BST-146; agents that promote glycemic control, suchas insulin, metformin, and thiazolidinediones; and anti-hypertensivessuch as angiotensin converting enzyme inhibitors (ACEI), angiotensin IIreceptor blockers (ARB), endothelin receptor antagonists and rennininhibitors. When administered as a combination, the therapeutic agentscan be formulated as separate compositions that are given at the sametime or different times, or the therapeutic agents can be given as asingle composition.

The compounds may be made up in a solid form (including granules,powders or suppositories) or in a liquid form (e.g., solutions,suspensions, or emulsions). The compounds of the invention may beapplied in a variety of solutions and may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc.

The compounds of the invention may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of the invention and apharmaceutically acceptable carrier. One or more compounds of theinvention may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of the invention may be in a form suitable for oraluse, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques. Insome cases such coatings may be prepared by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monosterate or glyceryl distearate maybe employed. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds and pharmaceutical compositions of the present inventionmay also be administered in the form of suppositories, e.g., for rectaladministration of the drug. These compositions can be prepared by mixingthe drug with a suitable non-irritating excipient that is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials includecocoa butter and polyethylene glycols.

Compounds and pharmaceutical compositions of the present invention maybe administered parenterally in a sterile medium. The drug, depending onthe vehicle and concentration used, can either be suspended or dissolvedin the vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.01 mg to about 50 mg perkilogram of body weight per day, more preferably between 0.1 mg to about50 mg per kilogram of body weight per day, and even more preferablybetween about 0.1 mg to about 20 mg per kilogram of body weight per dayare useful in the treatment of the above-indicated conditions. Theamount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofan active ingredient.

Pharmaceutical compositions containing the compounds described hereinare administered to an individual in need thereof. In a preferredembodiment, the subject is a mammal; in a more preferred embodiment, thesubject is a human. In therapeutic applications, compositions areadministered in an amount sufficient to carry out the methods of theinvention. Amounts effective for these uses depend on factors including,but not limited to, the nature of the compound (specific activity,etc.), the route of administration, the stage and severity of thedisorder, the weight and general state of health of the subject, and thejudgment of the prescribing physician. The active compounds areeffective over a wide dosage range. However, it will be understood thatthe amount of the compound actually administered will be determined by aphysician, in the light of the above relevant circumstances. Therefore,the above dosage ranges are not intended to limit the scope of theinvention in any way.

For administration to non-human mammals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate these animal feed and drinking water compositions so that theanimal ingests an appropriate quantity of the composition during a mealor throughout the course of the day. It may also be convenient topresent the composition as a premix for addition to the feed or drinkingwater.

Preparation of Compounds of the Invention

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art.

The reactions are performed in a solvent appropriate to the reagents andmaterials employed and suitable for the transformations being effected.It will be understood by those skilled in the art of organic synthesisthat the functionality present on the molecule should be consistent withthe transformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene and Wuts (Protective Groups In Organic Synthesis,Wiley and Sons, 1999). Suitable protecting groups include, but are notlimited to, tert-butoxycarbonyl (BOC), trimethylsilylethanesulfonamide(SES), benzyloxycarbonyl (CBZ) and benzyl (Bn) protecting groups.

One possible procedure to prepare compounds of the invention is shown inScheme 1. Imidazole compounds (003, R^(N′)═H) are synthesized byreaction of α-diketones (002) with pyridoxal hydrochloride (001) and asource of ammonia (NH₄OAc). If a primary amine (e-NH₂) is included inthe reaction, the N-functionalized product is formed. The hydroxymethylof 003 is converted to the halomethyl derivative (004) with SOCl₂(X′═Cl). Alternatively, reagents such as POCl₃, PCl₅, PCl₃, PPh₃ andCCl₄ (X′═Cl); SOBr₂, PPh₃ and CBr₄, PPh₃ and Br₂ (X′═Br); and PPh₃ andI₂ or N-iodosuccinimide (X′═I) may be utilized. Subsequently, thesubstitution of the halomethyl derivative (004) with a cyclic amineyields 005. If the imidazole nitrogen is unsubstituted (005, R^(N′)═H),it may be further substituted by reaction with a reagent of the formR^(N), —X′ or R^(N), —O—R^(N′) to yield compound 006. Examples ofappropriate reagents include, but are not limited to CH₃I, CF₃CH₂I,HOCH₂CH₂Br, CH₃(CO)Cl, (CF₃CO)O(COCF₃), (PhCO)O(COPh), and the like.

α-Diketones (002, Scheme 1) can be prepared by methods familiar to thoseskilled in the art. A few techniques are summarized in Scheme 2,involving one or two step procedures. The desired α-diketones may beprepared directly from alkenes by reaction with reagents such as KMnO₄in the presence of acetic anhydride or cupric sulfate. Alternatively,alkynes may be utilized with reagents such as KMnO₄ in the presence ofacetic acid or NaHCO₃ with MgSO₄; H₂O₂ and MeReO₃; NaOCl or NaIO₄ andcatalytic RuO₂; or PhIO and RuCl₂(PPh₃)₂. In two steps, symmetric orasymmetric (where two different aldehydes with different R³ groups areused) α-diols (0021) may be prepared from the corresponding aldehydesthrough the pinacol reaction. Appropriate reagents for the pinacolreaction include, but are not limited to Li, Na, TiCl₃, Zn and HCl, andSmI₂. The α-diols (0021) may oxidized to the corresponding α-diketone(002) with acetic anhydride or trifluoroacetic anhydride in DMSO; orwith NaOCl and catalytic 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy,free radical (4-methoxy-TEMPO).

Example 14-(4,5-Diethyl-1,1-imidazol-2-yl)-5-hydroxymethyl-2-methyl-pyridin-3-ol

Pyridoxal hydrochloride (2.03 g, 10 mmol) was dissolved in MeOH (25 mL)and cooled to 0-5° C. 3,4-Hexanedione (8.4 mL, 70 mmol) was added at0-5° C. and then aq. ammonium hydroxide solution (25%, 8 mL) keeping thetemperature between 5-10° C. The reaction mixture was warmed to rt andstirred over a period of 15 h. The suspension was filtered and thefiltrate was evaporated to distill off MeOH. Water (10 mL) was added andextracted with ethyl acetate (4×15 mL). The combined organic layers werewashed with water (10 mL), brine (10 mL), dried over Na₂SO₄ (5 g) andevaporated to dryness. The residue was suspended in ethyl acetate (10mL) and diethyl ether (20 mL) and stirred for 30 min. The suspension wasfiltered off, washed with diethyl ether (20 mL) and dried to give thetitle compound (920 mg) as yellow crystals.

Example 24-(4,5-Diphenyl-1H-imidazol-2-yl)-5-hydroxymethyl-2-methyl-pyridin-3-ol

Benzil (2.10 g, 10 mmol), ammonium acetate (11.5 g, 150 mmol) weredissolved in DMSO (60 mL) and heated to 100° C. Pyridoxal hydrochloride(4.1 g, 20 mmol) in DMSO (50 mL) was added drop wise and after 100 minstirring at 100° C. the reaction mixture was poured into icewater (300mL) and aq. ammonium hydroxide solution (50 mL). The precipitate wasfiltered off, washed with water (100 mL), dissolved in ethyl acetate(150 mL) and extracted with water (2×50 mL). The organic layer was driedover MgSO₄ (10 g) and evaporated to dryness. The residue was purified byflash chromatography on silica gel eluting with toluene/acetone 7/3.Fractions containing product were evaporated to a volume of 50 mL andcooled to 0° C. The precipitate was filtered off and dried to give (250mg) the title compound as a yellow solid.

Example 34-[4,5-Bis-(4-fluoro-phenyl)-1,1-imidazol-2-yl)-5-hydroxymethyl-2-methyl-pyridin-3-ol

4,4′-Difluorobenzil (2.46 g, 10 mmol), ammonium acetate (11.5 g, 150mmol) were dissolved in DMSO (60 mL) and heated to 100° C. Pyridoxalhydrochloride (6.1 g, 30 mmol) in DMSO (50 mL) was added drop wise overa period of 40 min. The reaction mixture was cooled to rt and pouredinto icewater (300 mL) and aq. ammonium hydroxide solution (50 mL). Theprecipitate was filtered off, washed with water (100 mL), dissolved inethyl acetate (150 mL) and extracted with water (2×50 mL). The organiclayer was dried over MgSO₄ (10 g) and evaporated to dryness. The residuewas purified by flash chromatography on silica gel eluting withtoluene/acetone 7/3. Fractions containing product were evaporated to avolume of 50 mL and cooled to 0° C. The precipitate was filtered off anddried to give (250 mg) the title compound as a yellow solid.

Example 44-(4,5-Di-furan-2-yl-1,1-imidazol-2-yl)-5-hydroxymethyl-2-methyl-pyridin-3-ol

α-Fluril (1.90 g, 10 mmol), ammonium acetate (11.5 g, 150 mmol) weredissolved in DMSO (60 mL) and heated to 100° C. Pyridoxal hydrochloride(6.1 g, 30 mmol) in DMSO (50 mL) was added drop wise over a period of 35min. The reaction mixture was cooled to rt and poured into icewater (300mL) and aq. ammonium hydroxide solution (50 mL). The precipitate wasfiltered off, washed with water (100 mL), dissolved in ethyl acetate(3×200 mL) and extracted with water (50 mL). The organic layer was driedover MgSO₄ (5 g) and evaporated to dryness. The residue was purified byflash chromatography on silica gel eluting with toluene/acetone 7/3.Fractions 13-18 were evaporated to a volume of 20 mL, the precipitatewas filtered off and dried to give (170 mg) a light beige solid.Fractions 19-44 were evaporated to a volume of 20 mL, the precipitatewas filtered off and dried to give (320 mg) the title compound as alight beige solid.

Example 5 5-(Chloromethyl)-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-olhydrochloride

5-(hydroxymethyl)-4-(1H-imidazol-2-yl)-2-methylpyridin-3-ol (5.1 g, 25mmol) was suspended in toluene (100 mL) and thionyl chloride (25 mL) wasadded. The suspension was heated to reflux for 2 h, cooled to 0° C. andfiltered. The title compound was obtained as brown solid (Purity by NMR:70-80%) and was used without further purification in the next step.

Example 64-(1H-Imidazol-2-yl)-2-methyl-5-[(4-methyl-1-piperazinyl)methyl-pyridin-3-ol

5-(chloromethyl)-4-(1H-imidazol-2-yl)-2-methylpyridin-3-ol hydrochloride(591 mg, 2 mmol) was suspended in methylene chloride (25 mL) andN-methyl piperazine (2.2 mL, 20 mmol) was added. After 20 h stirring atrt, the reaction mixture was evaporated to dryness. The residue waspurified twice by chromatography on silica gel eluting with methylenechloride/methanol 9/1. The title compound (150 mg) was obtained as redbrown oil.

Example 75-(Hydroxy-methyl)-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-pyridin-3-ol

5-(hydroxymethyl)-4-(1H-imidazol-2-yl)-2-methylpyridin-3-ol (1.03 g, 5.0mmol) was suspended in DMF (50 mL) and methyl iodide (0.31 mL, 5 mmol)was added at rt. The reaction mixture was stirred over a period of 19 hand a further portion of methyl iodide (0.125 mL, 2 mmol) was added andstirred over a period of 23 h. Aq. K₂CO₃ solution (10 mL) and water (50mL) was added and extracted with ethyl acetate (2×50 mL). Combinedorganic layers were dried over MgSO₄ (10 g) and evaporated to a volumeof 20 mL. After 3 days at room temperature, the crystallized product wasfiltered off and dried to give (600 mg) the title compound as a lightbeige solid.

Example 8 Redox Metal Ion Binding Affinity (Cu and Fe)

The AGE inhibition by these types of compounds is believed to occur whenthe compounds interfere with the role of the required redox metal ionsin the oxidative breakdown of the Amadori intermediates to advancedglycation end products (“glycoxidation”). We have measured the affinityof the compounds for cupric, ferrous and ferric ions in several cases byfollowing visible spectroscopic changes. These spectral titrationsusually involve adding varying amounts of compound to a fixed amount ofmetal ion in a suitable buffer having low metal ion affinity underphysiological pH conditions. In cases of extreme affinity, bindingconstants were estimated in a competitive assay mode. Table 1 providessome data that has been obtained in this way.

It will be noted that BST-605 is superior to BST-4997 in this regard,and the latter compound was superior to pyridoxamine. TheN-methylpiperazine side-chain of BST-4997 thus unexpectedly enhanced themetal ion binding affinity, which could not have been predicted apriori.

Binding affinity is measured as the dissociation constants K_(d) (unitsof concentration). All measurements were done by visible spectroscopy bymonitoring the spectrum of the complex formed by each compound near itswavelength maximum, which depends on the metal ion being studied. All Fewavelengths were 480 nm except for 430 nm for pyridoxamine.

TABLE 1 Cu²⁺ K_(d) Fe²⁺ K_(d) Fe³⁺ K_(d) Compound (μM) (mM) (mM)Pyridoxamine 39 +/− 15 49 +/− 9  59 +/− 13 BST-4997 1.13 +/− 0.09 0.69+/− 0.13 0.61 +/− 0.09 BST-605 0.13 +/− 0.04 0.72 +/− 0.14 0.52 +/− 0.04C-14547 7.01 +/− 1.69 BST-4996 0.59 +/− 0.11

Example 9 AGE Inhibition Efficacy In Vitro

Using a novel modification of the AGE Inhibition assay, we havedetermined the post-Amadori AGE inhibition potency for compounds ofinterest. The experiments were designed to determine the half-maximalinhibitory concentration of compounds (“IC50 values”) for inhibiting theconversion of Amadori intermediates to advanced glycation end products.The post Amadori AGE/CML ELISA assay has been developed to a 384 wellformat for rapidly testing potential inhibitors prepared from DMSOstocks. Assay signal to background ratios are high, at greater than20:1. Results in this format for AGE inhibitors agree well with previousdata, providing some measure of method validation, making the assay isrobust and reliable. Compounds for testing were dissolved at 100 mM ortheir maximum concentration in 100% DMSO. 100 mM is the DMSO stockconcentration necessary to detect potential inhibitors that have aneffective concentration similar to that of pyridoxamine. A subset ofcompounds were not fully soluble in DMSO at concentrations as low as 10mM. Due to low aqueous solubility, an initial screening of compounds wasusually carried out in dilute form across a 100 fold concentrationrange. Tested concentrations were from 0.2-20 μM to 2-200 μM, with thecompound concentration tested being dependent upon the originalsolubility in DMSO. When necessary, the activity of compounds wassubsequently confirmed in a more thorough repeat test against AGEformation from both RNase Amadori and BSA Amadori. Typically, from DMSOstocks, two stock plates were made. Each well contained 50 μL.

The stock plate #2 was then frozen at −20° C. during preparation. Later,stock plate #2 was removed from the freezer and allowed to thaw for 30minutes. The compounds in the plate were then mixed repeatedly with apipettor and diluted 5× into 0.01N HCl in H₂O.

Further dilutions were then carried out spanning two orders of magnitudeof concentration. After the compounds were diluted, 10 ul of phosphatebuffer was added to each well and mixed to neutralize the solutionbefore protein addition. Next 15 μL of 0.333 mg/mL of RNase-Amadori inphosphate buffer was added from a stock of ribose-RNAse prepared at 10.7mg/mL. These constitute the AGE reaction mixtures. All AGE reactionsproceeded for 20 hours at 37° C. Reactions were then diluted 50 foldinto coating buffer by 10× then 5× serial dilution. Coating proceeded at37° C. for two hours. Final protein was 0.1 μg/well in 384 well plates(2 μg/mL). ELISA was carried out similarly to before using the primaryantibody BST-3CK at 1:10000 dilution, and the secondary antibody labeledwith DELPHIA Europium GAR at 1:4000 dilution.

Pyridoxamine served as a reference to highlight the potency of BST-4997.In the present instance, the latter compound now serves as reference tohighlight the unanticipated greater potency of BST-605. Comparative dataare given in Table 2 below. The unexpected 6-fold potency of BST-605over BST-4997 (and 50-fold over pyridoxamine) contrasts with theobservation that the 5′-amino derivative C-14547 as well as the5′-acetamido derivative C-14521 had significantly weaker activity thanBST-4997. Thus introducing the nitrogen at the 5′-position in itselfdoes not account for the enhanced activity. The heterocyclic piperazinering thus provides the key to the enhancement, and we anticipate othersimilar rings would be advantageous.

TABLE 2 Compound IC₅₀ Potency Relative to BST-4997 Pyridoxamine   5 mM  0.12 BST-4997 0.6 mM (1) C-14521 2-3 mM 0.2-0.3 C-14547 1-2 mM 0.3-0.6BST-605 0.1 mM 6

Example 10 Cell Based Toxicity Assay

Hepatotoxicity is one of the major causes of drug failure in the clinic.HepG2 cells are human cells derived from a liver tumor, and express manyof the proteins and detoxification pathways of normal hepatocytes, andso make a reasonable model for initial cellular toxicity testing ofcandidate compounds. The test is based on the active conversion of3-[4,5-dimethylthiazol-2-yl]-2,5-dephenyltetrazolium bromide (MTT) bymitochondrial oxidation-reduction reactions into blue formazan crystals.Decreased crystal formation corresponds to decreased cell viability.Azide and chlorpromazine served as a positive controls

Need:

10×MTT stock solution (5 mg/ml MTT in 0.9% NaCl)0.04 N HCl in isopropanolCompound stocks: 100 mM in 100% DMSOMTT working solution: diluting 10×MTT stock into culture medium.Test article in cell culture medium ; Final DMSO concentration on thecells varies with the compound concentration (Final concentration ofsolvents such as DMSO should be kept at or below 1%)

Method:

-   -   1. Aspirate culture medium from HepG2cells. Replace culture        medium with test article dissolved in culture medium.    -   2. Incubate in 37° C., 5% CO₂ incubator for 16-24 hours.    -   3. Aspirate the medium from the cells; replace with an equal        volume of 37° C. MTT working solution.    -   4. Incubate for 3 hours.    -   5. Replace MTT solution with an equal volume of acidified        isopropanol.    -   6. Place solution in the refrigerator for 12-24 hours.    -   7. Place solution on an orbital shaker to dissolve any fomazan        precipitate.    -   8. Read the absorbance of the solution at 570 nm.

Several of the compounds of interest were tested at severalconcentrations for potential acute toxicity in the HepG2 cell-basedassay system. FIGS. 2 and 3 summarize the results of the assay; in allthese graphs, cell viability increases with bar height.

FIG. 2 provides comparative data for pyridoxamine (PM), BST-4997 (also,the free base of this compound which is referred to as BST-998), a5′-acetyl ester of BST-4997 (BST-146) which is rapidly hydrolyzed to theparent, and BST-605.

At a fixed concentration (1 mM), it was observed that BST-605 shows noacute toxicity in this assay, whereas BST-4997 shows some evidence oftoxicity.

Example 11 Maximum Tolerated Dose (MTD) Safety Study in Mice

A seven day repeat oral gavage study was carried out in male mice inorder to detect any obvious signs of clinical toxicity uponadministration of BST-605. For comparison, two groups were dosed withBST-4997 and BST-146 (acetyl ester of BST-4997 that is rapidlyhydrolyzed to parent BST-4997). Dosing was done daily at 10, 30 and 100mg/kg/day, and blood draws were taken at the end of study at 1, 2, 4 and8 h post-dosing.

The results confirmed that BST-4997 dosed animals suffered significanttoxicity at and above 30 mg/kg/day, leading to significant loss of theanimals. In contrast, no adverse clinical signs or gross examinationfindings were noted for any mice in the BST-605 dose groups. BST-605thus possesses marked superiority over BST-4997 with regard to in vivotoxicity and represents a significant advance.

Example 12 In Vivo Plasma Concentration and Metabolites

The plasma drawn from the mice in the above MTD study was examined by anHPLC fluorescence method for the presence of parent drug at differenttimes as well as for the possible presence of metabolites. A similarexamination was done for plasma samples from the fewer surviving micethat received BST-4997. An HPLC fluorescence method was developed toassay for parent drugs and possible metabolites of each drug. The HPLCmethod was further adapted for LC-MS/MS study by changing fromphosphoric acid to volatile 20 mM ammonium acetate. Parent drugs weredetected and quantified, and the plasma concentration that wasproportional to dose for BST-605 though not for BST-4997. This indicatesimproved pharmacokinetic behavior for BST-605.

Novel metabolites were detected and quantified for BST-605 and BST-4997,and their retention times and “concentrations” (assuming similarfluorescence to parents) were measured. Analysis of such metabolitesindicated that the parent compound had been oxidized and/or undergoneglucuronidation. Possible structures for the metabolites include thefollowing:

Example 13 Efficacy Study in STZ Rat Model of Diabetic Neuropathy

In vivo, BST-605 ameliorates diabetic complications in a STZ rat modelin proportion to its potency in the post-Amadori AGE inhibition assay.The STZ rat model has been described previously in WO 2004/019889. Ouraim was to ascertain whether BST-605 treatment could correct nervedysfunction in streptozotocin (STZ)-diabetic rats. Animals were madediabetic for 6 weeks, following which they were treated (n=6) for 2weeks with BST-605 given in the drinking water at concentrationsadjusted to correspond to doses of 0.22, 0.67 and 2.0 mg/kg/day. Theywere compared to control non-diabetic rats (n=10).

FIG. 3 provides the dose-response curve for restoration of nerveconduction velocity in motor (sciatic nerve) neurons, demonstratingefficacy at very low concentrations. Motor NCV was tested between thesciatic notch and knee for the nerve branch to tibialis anterior muscle,as described in Cameron et al., Q. J. Exp. Physiol. 74: 917-926 (1989);and Cameron et al., Exp. Neurol. 92: 757-761 (1986).

FIG. 4 provides the dose-response curve for restoration of nerveconduction velocity in sensory (saphenous) neurons, demonstratingefficacy at very low concentrations. Saphenous sensory NCV was measuredbetween the groin and ankle.

FIG. 5 compares BST-605 to BST-4997 and pyridoxamine showing theprogression in increased potency that follows the progression inpost-Amadori AGE inhibition.

We have further established a causal the link between administration ofsuch post-Amadori AGE inhibitors and therapeutic benefit by observingthat BST-4997 treated STZ rats demonstrated an actual decrease in AGElevels in the nerve vasculature. This was done by quantitativemeasurements of tissue staining for carboxymethyllysine (CML) AGEs,using anti-CML antibodies. A significant decrease in AGE staining wasobserved for animals treated with BST-4997 as compared to diabeticcontrols.

A determination of drug exposure was also made from plasma collectedfrom STZ rats at sacrifice that were dosed at the lowest two doses. Drugexposure was observed and measured for BST-605, and its majormetabolites were detected. The detection of parent drugs and metabolitesin the STZ rat, as in the mice plasma, confirms that sufficient exposureto the drug occurred in the studies so as to make the toxicity findingsand in vivo efficacy reflective of drug administration.

It is understood that the foregoing detailed description andaccompanying Examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined by theappended claims. Various changes and modifications to the disclosedembodiments will be apparent to those skilled in the art. Such changesand modifications, including without limitation those relating to thechemical structures, substituents, derivatives, intermediates,syntheses, formulations and/or methods of use of the invention, may bemade without departing from the spirit and scope thereof.

1. A compound of the formula,

or a pharmaceutically acceptable salt thereof, wherein X is N, N—O, orCR¹; G is —H, heterocycle, or —(C₁-C₆)alkyl, wherein the heterocycle andalkyl are optionally substituted with at least one group independentlyselected from the group consisting of -halogen, —OR^(G), —N(R^(G))₂,—SR^(G), —S(O)R^(G), —S(O)₂R^(G), —COOR^(G), —CON(R^(G))₂, and—(C₁-C₆)alkyl-OR^(G), wherein R^(G) is hydrogen, —(C₁-C₆)alkyl, or—C(O)(C₁-C₆)alkyl; A is of the formula,

wherein Y is N or N-oxide; and ring C is: (i) monocyclic; (ii)saturated; and (iii) contains 1 or 2 total heteroatoms, and 5 or 6 totalatoms, wherein the remaining heteroatom moiety is O, S, or NR^(N1), andthe carbon atoms are each optionally substituted with one or two R^(C)wherein R^(N1) is —H, -oxide, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl,—(C₃-C₈)cycloalkyl, -heterocycle, -aryl, -heteroaryl,—(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl, -heteroaroyl,—(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl, wherein  R^(N1)is optionally substituted with one or more groups which areindependently -halogen, —OR^(N12), —N(R^(N12))₂, —COOR^(N12)—,—CON(R^(N12))₂, —SR^(N12), —S(O)R^(N12), —S(O)₂R^(N12), —NO₂, —CN,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-OR^(N12), -aryl, —(C₁-C₆)haloalkyl,—(C₃-C₈)cycloalkyl, —(C₁-C₆)alkanoyl, or -aroyl, wherein R^(N12) ishydrogen, —(C₁-C₆)alkyl, or —C(O)(C₁-C₆)alkyl; each R^(C) isindependently —Z¹-M-Z²—R^(Z), wherein M is —C(O)—, —C(S)—, —S(O)—,—S(O)₂—, or absent, provided when M is −S(O)—, —S(O)₂—, or absent, atleast one of Z¹ and Z² is also absent; Z¹ and Z² are independently —O—,—S—, —N(R^(N′))—, or absent, wherein R^(N′) is —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl,—(C₃-C₈)cycloalkyl, -heterocycle, -aryl, -heteroaryl,—(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl, -heteroaroyl,—(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl, wherein  R^(N′)is optionally substituted with one or more groups which areindependently -halogen, —OR, —COOK, —CONR₂, —SR, —S(O)R, —S(O)₂R, —NR₂,—NO₂, —CN, —(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl,—(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl, or -aroyl wherein each R is independently —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, orheteroaryl, wherein the alkyl and alkoxy are optionally substituted withone or more R′;  wherein each R′ is independently halogen, —OR″, —CN,—COR″, —COOR″, —CONR″₂, NR″₂, wherein  each R″ is independently —H,—(C₁-C₆)alkyl, or —(C₁-C₆)haloalkyl; R^(Z) is —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl,—(C₁-C₆)alkylaryl, -heterocycle, -aryl, or -heteroaryl, wherein R^(Z) isoptionally substituted with at least one R^(Z)', wherein  each R^(Z′) isindependently -halogen, —OR, —(C₁-C₆)alkoxy, —C(O)OR, —C(O)R, —C(O)NR₂,—S(O)₂R, —OS(O)₂R, -cyano, -nitro, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₈)cycloalkyl, -heterocycloalkyl, or heteroaryl,  wherein R^(Z′) isoptionally substituted with one or more R′, or any two R^(C) attached tothe same carbon, taken together, is oxo or ═N(R^(N4)), wherein R^(N4) isit —H, —OR, —N(R^(N5))₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl,—(C₃-C₈)cycloalkyl, -heterocycle, -aryl, or -heteroaryl, wherein R^(N4)is optionally substituted with one or more groups which areindependently -halogen, —OH, -amino, —(C₁-C₆)alkylamino,—(C₁-C₆)dialkylamino, —NO₂, —CN, —(C₁-C₆)alkyl, -aryl, -heteroaryl,-heterocycle, —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,—(C₁-C₆)alkanoyl, or -aroyl; and each R^(N5) is independently —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl,—(C₁-C₆)alkanoyl, or —(C₃-C₈)cycloalkyl; B is of the formula,

wherein ring D is (i) monocyclic, and (ii) saturated, unsaturated, oraromatic; R^(C′) is R^(C), provided that R^(C′) is not aryl orheteroaryl; G¹, G², and G³ each are independently N, O, CR³, C(R³)₂, orNR^(N′), wherein each R³ is independently —Z³-M-Z⁴—R^(Z), provided whenM is —S(O)—, —S(O)₂—, or absent, at least one of Z³ and Z⁴ is alsoabsent; Z³ and Z⁴ are independently —O—, —S—, —N(R^(N3))— or absent,wherein R^(N3) is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₁-C₆)alkynyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkanoyl,-heterocycloyl, -aroyl, -heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or-aryl(C₁-C₆)alkoxycarbonyl, wherein  R^(N3) is optionally substitutedwith one or more groups which are independently -halogen, —OH, -amino,—(C₁-C₆)alkylamino, —(C₁-C₆)dialkylamino, —NO₂, —CN, —(C₁-C₆)alkyl,-aryl, -heterocycle, -heteroaryl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl,—(C₁-C₆)alkoxy, —(C₁-C₆)alkanoyl, or -aroyl; or two R³ taken togetherare oxo; and bonds a, b, c, d, and e are independently a single ordouble bond, provided that (i) no two consecutive atoms in ring D areboth oxygen; (ii) no two consecutive bonds are both double bonds; (iii)if a orb is a double bond, then R^(C′) is absent; and (iv) if a or e isa double bond, then R^(N′) is absent; and R², and R⁶ are independently—H, -halogen, —NO₂, —CN, or R^(C), provided that when X═CR¹, (i) R², R⁶,and R^(N1) are not phenyl; (ii) R^(C) is not aryl, heteroaryl,heterocycle, or (C₂-C₆)alkenyl (iii) and G¹═N together, then G₂ is notO; and (iv) two R^(C) together may not form oxo; and provided that whenX═N, and (i) G¹ and G³ each are CR³, G²═N, and bonds b and d are each adouble bond, all simultaneously; or (ii) G¹ is CR³, G³ is C(O), G² isNe, and bond b is a double bond, all simultaneously; either R² or R⁶ isnot —NH-aryl or —NH-heteroaryl.
 2. The compound according to claim 1,wherein X is N and G is hydrogen.
 3. The compound according to claim 2,wherein B is aromatic; and G′, G², and G³ are each independently O, N orCR³.
 4. The compound according to claim 3, wherein B is imidazolyl,oxazoyl, pyrazoyl, pyrroyl, or isoxazoyl wherein each carbon atom issubstituted by R³.
 5. The compound according to claim 4, wherein B isimidazolyl wherein each carbon atom is substituted by R³.
 6. Thecompound according to claim 5, wherein each R³ is independently R^(Z3),wherein R^(Z3) is —H, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle, -aryl, or-heteroaryl, wherein R^(Z3) is optionally substituted with at least oneR^(Z3′), wherein each R^(Z3′) is independently -halogen, -cyano, —OR,—C(O)OR, —C(O)R, —C(O)NR₂, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₈)cycloalkyl, or -heterocycloalkyl.
 7. The compound according toclaim 5, wherein R² and R⁶ are each —H, -halogen, —NO₂, —CN, or —R^(Z6)wherein R^(Z6) is —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl,—(C₁-C₆)alkylaryl, -heterocycle, -aryl, or -heteroaryl, wherein R^(Z6)is optionally substituted with at least one R^(Z6′), wherein eachR^(Z6′) is independently -halogen, —OR, —C(O)OR, —C(O)R, —(C₁-C₆)alkyl,or —(C₁-C₆)haloalkyl, wherein R^(Z6′) is optionally substituted with oneor more R′.
 8. The compound according to claim 5, wherein R^(N′) is —H,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl,-aryl, -heteroaryl, —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,-heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl,wherein R^(N′) is optionally substituted with one or more groups whichare independently -halogen, —OR^(N″), —NR^(N″) ₂, —NO₂, —CN,—(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl, —(C₃-C₈)cycloalkyl, or—(C₁-C₆)haloalkyl, wherein each R^(N″) is independently —H,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,-heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl and alkoxy areoptionally substituted with one or more R′.
 9. The compound according toclaim 5, wherein ring C contains 2 heteroatoms, and 5 total atoms,wherein the remaining heteroatom moiety is O, S, or NR^(N1), and thecarbon atoms are each optionally substituted with one or two R^(C). 10.The compound according to claim 5, wherein ring C contains 2heteroatoms, and 6 total atoms, wherein the remaining heteroatom moietyis O, S, or NR^(N1), and the carbon atoms are each optionallysubstituted with one or two R^(C).
 11. The compound according to claim2, wherein B is not aromatic and G¹, G², and G³ are each independentlyO, N, CR³, C(R³)₂, or N(R^(N′)).
 12. The compound according to claim 12,wherein B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl, whereineach carbon is substituted by two R³ and each nitrogen is substituted byR^(N′).
 13. The compound according to claim 12, wherein each R³ isindependently R^(Z3), wherein R^(Z3) is —H, —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,-aryl, or -heteroaryl, wherein R^(Z3) is optionally substituted with atleast one R^(Z3′), wherein each R^(Z3′) is independently -halogen,-cyano, —OR, —C(O)OR, —C(O)R, —C(O)NR₂, —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, or -heterocycloalkyl.
 14. Thecompound according to claim 12, wherein R² and R⁶ are each —H, -halogen,—NO₂, —CN, or —R^(Z6) wherein R^(Z6) is —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,-aryl, or -heteroaryl, wherein R^(Z6) is optionally substituted with atleast one R^(Z6′), wherein each R^(Z6′) is independently -halogen, —OR,—C(O)OR, —C(O)R, —(C₁-C₆)alkyl, or —(C₁-C₆)haloalkyl, wherein R^(Z6′) isoptionally substituted with one or more R′.
 15. The compound accordingto claim 12, wherein each R^(N′) is —H, —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl, -aryl,-heteroaryl, —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,-heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl,wherein R^(N′) is optionally substituted with one or more groups whichare independently -halogen, —OR^(N″), —NR^(N″) ₂, —NO₂, —CN,—(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl, —(C₃-C₈)cycloalkyl, or—(C₁-C₆)haloalkyl, wherein each R^(N″) is independently —H,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,-heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl and alkoxy areoptionally substituted with one or more R′.
 16. The compound accordingto claim 12, wherein ring C contains 2 heteroatoms, and 5 total atoms,wherein the remaining heteroatom moiety is O, S, or NR^(N1), and thecarbon atoms are each optionally substituted with one or two R^(C). 17.The compound according to claim 12, wherein ring C contains 2heteroatoms, and 6 total atoms, wherein the remaining heteroatom moietyis O, S, or NR^(N1), and the carbon atoms are each optionallysubstituted with one or two R^(C).
 18. The compound according to claim1, wherein X is CR¹ and G is hydrogen.
 19. The compound according toclaim 18, wherein R¹ is —CN, —NO₂, -halogen, —C(O)OR⁴, —C(O)R⁴,—C(O)N(R⁴)₂, —S(O)R⁴, —S(O)₂R⁴, or —S(O)₂N(R⁴)₂, wherein each R⁴ isindependently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₃-C₈)cycloalkyl,-(Q-C₆)alkylaryl, -heterocycle, -aryl, or -heteroaryl, wherein R⁴ isoptionally substituted with at least one group, each of which areindependently -halogen, —OH, —(C₁-C₆)alkoxy, —C(O)R⁴¹, —S(O)₂R⁴¹,—OS(O)₂R⁴¹, -cyano, -nitro, -(C₁-C₆)alkyl, or -(Q-C₆)haloalkyl,  whereinR⁴¹ is —H, -(Q-C₆)alkyl, —(C₁-C₆)haloalkyl, -(Q-C₆)alkoxy,—(C₃-C₈)cycloalkyl, -heterocycloalkyl, aryl, or heteroaryl.
 20. Thecompound according to claim 19, wherein B is aromatic; and G¹, G², andG³ are each independently O, N or CR³.
 21. The compound according toclaim 20, wherein B is imidazolyl, oxazoyl, pyrazoyl, pyrroyl, orisoxazoyl wherein each carbon atom is substituted by R³.
 22. Thecompound according to claim 21, wherein B is imidazolyl wherein eachcarbon atom is substituted by R³.
 23. The compound according to claim22, wherein each R³ is independently R⁷³, wherein R^(Z3) is —H,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl,-heterocycle, -aryl, or -heteroaryl, wherein R^(Z3) is optionallysubstituted with at least one R^(Z3′), wherein each R^(Z3′) isindependently -halogen, -cyano, —OR, —C(O)OR, —C(O)R, —C(O)NR₂,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, or-heterocycloalkyl.
 24. The compound according to claim 22, wherein R²and R⁶ are each —H, -halogen, —NO₂, —CN, or —R^(Z6) wherein R^(Z6) is—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl,-heterocycle, -aryl, or -heteroaryl, wherein R² is optionallysubstituted with at least one R^(Z6′), wherein each R^(Z6′) isindependently -halogen, —OR, —C(O)OR, —C(O)R, —(C₁-C₆)alkyl, or—(C₁-C₆)haloalkyl, wherein R^(Z6′) is optionally substituted with one ormore R′.
 25. The compound according to claim 22, wherein R^(N′) is —H,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl,-aryl, -heteroaryl, —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,-heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl,wherein R^(N′) is optionally substituted with one or more groups whichare independently -halogen, —OR^(N″), —NR^(N″) ₂, —NO₂, —CN,—(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl, —(C₃-C₈)cycloalkyl, or—(C₁-C₆)haloalkyl, wherein each R^(N″) is independently —H,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,-heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl and alkoxy areoptionally substituted with one or more R′.
 26. The compound accordingto claim 22, wherein ring C contains 2 heteroatoms, and 5 total atoms,wherein the remaining heteroatom moiety is O, S, or NR^(N1), and thecarbon atoms are each optionally substituted with one or two R^(C). 27.The compound according to claim 22, wherein ring C contains 2heteroatoms, and 6 total atoms, wherein the remaining heteroatom moietyis O, S, or NR^(N1), and the carbon atoms are each optionallysubstituted with one or two R^(C).
 28. The compound according to claim19, wherein B is not aromatic and G¹, G², and G³ are each independentlyO, N, CR³, C(R³)₂, or N(R^(N′)).
 29. The compound according to claim 28,wherein B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,isoxazolidinyl, oxazolidinyl, triazolidinyl, or tetrazolidinyl, whereineach carbon is substituted by two R³ and each nitrogen is substituted byR^(N′).
 30. The compound according to claim 29, wherein each R³ isindependently R^(Z3), wherein R^(Z3) is —H, —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,-aryl, or -heteroaryl, wherein R^(Z3) is optionally substituted with atleast one R^(Z3′), wherein each R^(Z3′) is independently -halogen,-cyano, —OR, —C(O)OR, —C(O)R, —C(O)NR₂, —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, or -heterocycloalkyl.
 31. Thecompound according to claim 29, wherein R² and R⁶ are each —H, -halogen,—NO₂, —CN, or —R^(Z6) wherein R^(Z6) is —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₈)cycloalkyl, —(C₁-C₆)alkylaryl, -heterocycle,-aryl, or -heteroaryl, wherein R^(Z6) is optionally substituted with atleast one R^(Z6′), wherein each R^(Z6′) is independently -halogen, —OR,—C(O)OR, —C(O)R, —(C₁-C₆)alkyl, or —(C₁-C₆)haloalkyl, wherein R^(Z6′) isoptionally substituted with one or more R′.
 32. The compound accordingto claim 29, wherein each R^(N′) is independently —H, —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)alkanoyl, —(C₃-C₈)cycloalkyl, -aryl,-heteroaryl, —(C₃-C₈)cycloalkanoyl, -heterocycloyl, -aroyl,-heteroaroyl, —(C₁-C₆)alkoxycarbonyl, or -aryl(C₁-C₆)alkoxycarbonyl,wherein R^(N′) is optionally substituted with one or more groups whichare independently -halogen, —OR^(N″), —NR^(N″) ₂, —NO₂, —CN,—(C₁-C₆)alkyl, -aryl, -heterocycle, -heteroaryl, —(C₃-C₈)cycloalkyl, or—(C₁-C₆)haloalkyl, wherein each R^(N″) is independently —H,—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,-heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl and alkoxy areoptionally substituted with one or more R′.
 33. The compound accordingto claim 29, wherein ring C contains 2 heteroatoms, and 5 total atoms,wherein the remaining heteroatom moiety is O, S, or NR^(N1), and thecarbon atoms are each optionally substituted with one or two R^(C). 34.The compound according to claim 29, wherein ring C contains 2heteroatoms, and 6 total atoms, wherein the remaining heteroatom moietyis O, S, or NR^(N1), and the carbon atoms are each optionallysubstituted with one or two R^(C).
 35. The compound according to claim 1which is4-(1H-imidazol-2-yl)-2-methyl-5-((4-methylpiperazin-1-yl)methyl)pyridin-3-ol.36. A pharmaceutical composition comprising the compound of claim 1 anda pharmaceutically acceptable carrier.
 37. A method for treating orinhibiting development of one or more AGE- and/or ALE-associatedcomplications in subject in need thereof comprising administering one ormore compounds according to claim 1 to the subject.
 38. A method fortreating or inhibiting development of one or more AGE- and/orALE-associated complications in a subject in need thereof comprisingadministering one or more pharmaceutical compositions according to claim26 to the subject.
 39. The method of claim 37 wherein the one or moreAGE- and/or ALE-associated complications are selected from the groupconsisting of accelerated protein aging, retinopathy, nephropathy,proteinuria, impaired glomerular clearance, neuropathy, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, atherosclerosis,cardiovascular disease, neurodegenerative amyloid diseases,diabetes-associated hyperlipidemia, oxidative modification of proteins,arthritis, connective tissue diseases, amyloidosis, urinary stonedisease, obesity-related complications, proliferation of smooth musclecells in the aorta, coronary artery occlusion, hypertension; anddialysis-related disorders selected from the group consisting ofdialysis-related cardiac morbidity and mortality, dialysis-relatedamyloidosis, dialysis-related increases in permeability of theperitoneal membrane in a dialysis patient, renal failure progression ina dialysis patient, and ultrafiltration failure and peritoneal membranedestruction in a dialysis patient.
 40. A method for treating orinhibiting development of one or more disorders selected from the groupconsisting of diabetic nephropathy, proteinuria, impaired glomerularclearance, retinopathy, neuropathy, atherosclerosis, diabetes-associatedhyperlipidemia, oxidative modification of proteins, arthritis,connective tissue diseases, amyloidosis, urinary stone disease,obesity-related complications proliferation or smooth muscle cells inthe aorta, coronary artery occlusion, and hypertension; anddialysis-related disorders including dialysis-related cardiac morbidityand mortality, dialysis-related amyloidosis, dialysis-related increasesin permeability of the peritoneal membrane in a dialysis patient, renalfailure progression in a dialysis patient, and inhibitingultrafiltration failure and peritoneal membrane destruction in adialysis patient, wherein the method comprises administering aneffective amount of a compound according to claim 1 to a subject in needof such treatment.
 41. A method for treating or inhibiting developmentof one or more disorders selected from the group consisting of diabeticnephropathy, proteinuria, impaired glomerular clearance, retinopathy,neuropathy, atherosclerosis, diabetes-associated hyperlipidemia,oxidative modification of proteins, arthritis, connective tissuediseases, amyloidosis, urinary stone disease, obesity-relatedcomplications proliferation or smooth muscle cells in the aorta,coronary artery occlusion, and hypertension; and dialysis-relateddisorders including dialysis-related cardiac morbidity and mortality,dialysis-related amyloidosis, dialysis-related increases in permeabilityof the peritoneal membrane in a dialysis patient, renal failureprogression in a dialysis patient, and inhibiting ultrafiltrationfailure and peritoneal membrane destruction in a dialysis patient,wherein the method comprises administering an effective amount of apharmaceutical composition according to claim 36 to a subject in need ofsuch treatment.